The chimeric antigen receptor (CAR) provides a promising approach for adoptive T-cell immunotherapy for cancer. Commonly, CARs comprise a single chain fragment variable (scFv) of an antibody specific for a tumor associated antigen (TAA) coupled via hinge and transmembrane regions to cytoplasmic domains of T-cell signaling molecules. The most common lymphocyte activation moieties include a T-cell costimulatory (e.g. CD28, CD137, OX40, ICOS, and CD27) domain in tandem with a T-cell triggering (e.g. CD3ζ) moiety. The CAR-mediated adoptive immunotherapy allows CAR-grafted T cells to directly recognize the TAAs on target tumor cells in a non-HLA-restricted manner.
Most patients with acute myeloid leukemia (AML) are incurable with standard therapy; in addition, available treatment options are toxic. Redirecting T cells to recognize a target to which they had previously been blind may be one way to harness the power of the immune system to treat AML. Chimeric antigen receptor (CAR) modified autologous T cell (CART) therapy relies on redirecting T cells to a suitable cell-surface molecule on AML cells.
CAR therapies have been clinically successful in targeting CD19 for the control of B cell malignancy. However, therapeutic strategies for the treatment of myeloid leukemias are currently limited. Folate receptor beta (FRβ) is a GPI-anchored membrane protein with limited expression on normal tissues, restricted to a small population of mature hematopoietic subsets, but expressed on over 70% of primary Acute AML samples.
There is a need in the art for a CAR based therapy that targets folate receptor beta. The present invention addresses this unmet need in the art.